First report of carglumic acid in a patient with citrullinemia type 1 (argininosuccinate synthetase deficiency)

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1 Received: 14 June 2017 Accepted: 20 June 2017 DOI: /jcpt CASE REPORT First report of carglumic acid in a patient with citrullinemia type 1 (argininosuccinate synthetase deficiency) E. Kose MD 1 P. Kuyum MD 2 B. Aksoy MD 2 J. Ha berle MD 3 N. Arslan MD, PhD 1 Y. Ozturk MD 2 1 Division of Pediatric Metabolism and Nutrition, Dokuz Eylul University, Izmir, Turkey 2 Division of Pediatric Gastroenterology, Dokuz Eylul University, Izmir, Turkey 3 Division of Metabolism and Children s Research Center, University Children s Hospital Zurich, Zurich, Switzerland Correspondence N. Arslan, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, Izmir Biomedicine and Genome Center (ibg-izmir), Dokuz Eylul University Faculty of Medicine, Izmir, Turkey. nur.arslan@deu.edu.tr Funding information Swiss National Science Foundation, Grant/ Award Number: _ Summary What is known and objective: Carglumic acid is a structural analogue of human N- acetylglutamate, which has become an alternative therapeutic option for hyperammonaemia in organic acidaemias such as isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia, and it has been suggested in other urea cycle disorders such as ornithine transcarbamylase deficiency and carbamoyl phosphate synthetase 1 deficiency. Case description: A male newborn was diagnosed with citrullinemia after serum amino acid analyses revealed markedly elevated citrulline concentration together with homozygous p.gly390arg mutation in ASS1 gene. The ammonia concentration decreased and blood gas analysis normalized after peritoneal dialysis was performed for three days. Also, sodium benzoate, L- arginine and parenteral nutrition with glucose and lipid therapy were initiated. Until 1 year of age, low adherence to sodium benzoate therapy due to unpleasant taste caused hyperammonaemic episodes and obligated us to initiate carglumic acid (100 mg/kg/day) therapy. During treatment with carglumic acid, the median ammonia level was 45.6 µmol/l. The patient s treatment was switched from carglumic acid to sodium phenylbutyrate when he was 4.5 years old. Currently, the patient is 6.5 years old and remains under follow- up with sodium phenylbutyrate, L- arginine and protein- restricted diet. Plasma ornithine level was found to be significantly lower during the carglumic acid treatment compared to other treatments (P=.039). Also, glutamic acid was found to be higher during the sodium benzoate treatment period compared to other treatment periods (P=.024). What is new and conclusion: To the best of our knowledge, this is the first report describing the long- term use of carglumic acid in a patient with argininosuccinate synthetase deficiency. KEYWORDS argininosuccinate synthetase deficiency, carglumic acid, citrullinemia type 1, hyperammonaemia 1 WHAT IS KNOWN AND OBJECTIVE Ammonia detoxification through the urea cycle is the major route for nitrogen disposal as urea excreted in the urine (Figure 1). Several inborn errors of metabolism, such as primary urea cycle disorders (UCDs) and organic acidaemias, fatty acid oxidation defects, disorders of amino acid metabolism and valproate can cause increased blood ammonia levels. 1 Hyperammonaemia is a condition which may result in neurological complications, coma and even death John Wiley & Sons Ltd wileyonlinelibrary.com/journal/jcpt J Clin Pharm Ther. 2018;43:

2 KOSE et al. 125 FIGURE 1 The urea cycle pathway. GS, glutamine synthetase; GD, glutamate dehydrogenase; CPS, carbamoyl phosphate synthetase 1; NAGS, N- acetylglutamate synthase; NAG, N- acetylglutamate; OTC, ornithine transcarbamylase; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase; ARG, arginase Treatment of hyperammonaemia in patients with UCDs includes dietary protein restriction to reduce nitrogen flux, and administration of ammonia scavenger medications such as sodium benzoate, sodium phenylacetate and sodium or glycerol phenylbutyrate to divert excess nitrogen into a non- toxic, excretable metabolite pool. 2 Carglumic acid, a structural analogue of human N- acetylglutamate (NAG), has been used for the treatment of N- acetylglutamate synthase (NAGS) deficiency. 3 By directly replacing NAG, which is an essential activator of carbamoyl phosphate synthetase 1 (CPS1), carglumic acid offers an almost curative medication for NAGS deficiency. Additionally, given its capacity to function as a urea cycle activator, carglumic acid has been proposed as a potential therapy for secondary hyperammonaemia resulting from organic acidaemias, hepatic encephalopathy and valproate- induced hyperammonaemia. 4 Recently, it has been proposed that carglumic acid may have clinical efficacy for other UCDs, such as ornithine transcarbamylase (OTC) deficiency and CPS1 deficiency. 5,6 There is no information about the clinical use of carglumic acid in other UCDs. In this case report, we present a 6.5- year- old male patient with citrullinemia type 1 (argininosuccinate synthetase deficiency) who was successfully treated for 3.5 years with carglumic acid. This is the first case of citrullinemia type 1 in the literature for whom follow- up was performed with carglumic acid treatment, and this report provides insight on the efficacy of carglumic acid in the long- term treatment of citrullinemia type 1. 2 CASE DESCRIPTION A male newborn was admitted to hospital at the age of 9 days with complaints of restlessness, feeding problems and vomiting. The child weighing 4030 g was born to third- degree consanguineous parents after a full- term, uneventful pregnancy. His history during the

3 126 KOSE et al. antenatal period and in the first week of life was unremarkable. There was no history of genetic disease, early infant death or congenital abnormalities in his family. The patient was pale, lethargic and dehydrated at the time of admission. No dysmorphic appearance was noted. In the physical examination, tachypnea and tachycardia were detected. Other system examinations were normal. Laboratory investigations showed hyperammonaemia (393.3 μmol/l) and partially compensated metabolic acidosis (ph: 7.4, pco 2 : 22.4 mm Hg, HCO 3 : 14.5 mmol/l). Serum sodium, urea, creatinine and electrolyte levels and complete blood count were within normal range. He was diagnosed with citrullinemia after serum amino acid analyses revealed markedly elevated citrulline concentration at 2752 μmol/l (reference range [rr]: 5-55) together with elevated glutamine (1165 μmol/l, rr: ) and urine orotic acid (26.9 mmol/mol creatinine, rr: 0-5.3) concentrations. Homozygous c.1168g>a (p.gly390arg) mutation in ASS1 gene was detected by means of molecular genetic investigation. The ammonia concentration decreased and blood gas analysis normalized after peritoneal dialysis was performed for 3 days. Also, sodium benzoate (250 mg/kg/day), L- arginine (250 mg/kg/day), and parenteral nutrition with glucose and lipid therapy were initiated. At the age of 11 days, his plasma ammonia concentration decreased to below 71.4 μmol/l. He remained under follow- up with sodium benzoate, L- arginine and protein- restricted diet. At 1 year of age, low adherence to sodium benzoate therapy due to its unpleasant taste and failure to supply phenylbutyrate and glycerol phenylbutyrate obligated us to initiate therapy with carglumic acid (Carbaglu ; Orphan Europe, Puteaux, France) (100 mg/kg/day, orally twice daily for 1 week, maintenance dose was of 50 mg/kg/day, orally twice daily) (Figure 2). In FIGURE 2 Analysis of plasma ammonia, citrulline, glutamic acid, glycine and ornithine levels of the patient. Treatment periods are indicated as months (*: infection period)

4 KOSE et al. 127 the first year of life, the median plasma ammonia level (after diagnostic plasma ammonia levels, which were elevated and skewed the data, were excluded) was 61.4 μmol/l. Carglumic acid therapy was well tolerated, and the patient did not experience any hyperammonaemic crisis up to 4.5 years of age except during infection periods (at 20, 45 and 55 months of life; Figure 2). During treatment with carglumic acid, the median ammonia level (plasma ammonia levels during infections were excluded) was 45.6 μmol/l. Owing to the high cost of carglumic acid and tolerable taste of sodium phenylbutyrate (Pheburane, Lucane Pharma, Paris, France), the patient s treatment was switched from carglumic acid to sodium phenylbutyrate (250 mg/kg/day) when he was 4.5 years old. Currently, the patient is 6.5 years old and remains under follow- up with sodium phenylbutyrate, L- arginine and protein- restricted diet. During sodium phenylbutyrate treatment, median plasma ammonia level remained low at 30.7 μmol/l. 2.1 Laboratory findings Plasma ammonia, citrulline, glutamic acid, glycine and ornithine levels of the patient from the time of citrullinemia diagnosis to date are shown in Figure 2. In the analysis of laboratory findings of the patient, there were no differences in median ammonia, citrulline and glycine levels between the sodium benzoate, carglumic acid and sodium phenylbutyrate treatments. Ornithine level was found to be significantly lower during the carglumic acid treatment compared to other treatments (P=.039). Also, glutamic acid was found to be higher during the sodium benzoate treatment period compared to other treatment periods (P=.024). Carglumic acid is a structural analogue of human NAG which can enter mitochondria to induce CPS1, enhancing the activity of the urea cycle and promoting ureagenesis. It has been recently approved for the acute and chronic management of patients with NAGS deficiency. 3 Within the last 5 years, carglumic acid has become an alternative therapeutic option for hyperammonaemia in organic acidaemias, such as isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia. 7-9 Apart from inborn errors of metabolism, it is also used for valproate- induced hyperammonaemia. 10,11 Furthermore, it has been proposed that carglumic acid may have clinical efficacy in other UCDs such as OTC and CPS1 deficiencies. 5,6 The recommended initial dose for acute hyperammonaemia is 100 mg/kg/day to 250 mg/kg/day. 12 There is no consensus about the maintenance dose of carglumic acid treatment Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. We determined the initial dose as 100 mg/kg/day; after 1 week, the maintenance dose became 50 mg/kg/day. Possible side effects of carglumic acid were mentioned as vomiting, abdominal pain, fever, inflammation of tonsil, reduced red cells in blood, ear infection, diarrhoea and headache. 14 In our case, no adverse effects were noted during treatment. To the best of our knowledge, the case presented herein is the first citrullinemia type 1 patient treated with carglumic acid. Moreover, this case suggests that carglumic acid may be safely used in citrullinemia type 1 (argininosuccinate synthetase deficiency), in which the main goal of treatment is to lower plasma ammonia level (<65 μmol/l). In the comparison of three treatments (sodium benzoate, carglumic acid, sodium phenylbutyrate), no difference was detected in plasma ammonia levels, and ammonia levels were in the normal range with the carglumic acid treatment except infection periods. The mechanism by which carglumic acid improves metabolic stability remains speculative. We hypothesize that by activating CPS1, flux through the urea cycle can be improved, allowing better ammonia handling in citrullinemia type 1. However, this hypothesis should be tested using stable isotope- based quantification of ureagenesis. 15 This test, although available in some centres, was unfortunately not accessible to us during treatment with carglumic acid in this patient. Sodium benzoate provides an alternative pathway to the urea cycle for the removal of nitrogen waste by interacting with glycine to form hippurate, which is excreted by the kidneys (Figure 1). 16 Although decreased plasma glycine levels were expected during the treatment with sodium benzoate, no difference was observed in plasma glycine levels compared to other treatments. Sodium phenylbutyrate is a prodrug of phenylacetate, which undergoes rapid β- oxidation to form phenylacetate in the liver after absorption. Phenylacetate is metabolically coupled with glutamine and therefore increases the excretion of this ammoniagenic amino acid. Clearance of glutamine as phenylacetylglutamine by the kidneys activates the glutamine synthetase enzyme to catalyse the condensation of glutamic acid and ammonia to form glutamine and leads to decreased plasma levels of glutamic acid (Figure 1). 16 In our patient, consistent with the literature, lower levels of plasma glutamic acid were seen with sodium phenylbutyrate treatment compared to sodium benzoate treatment. Moreover, significantly decreased plasma glutamic acid levels were detected during the treatment with carglumic acid. This finding suggests that activated CPS1 decreases the plasma levels of ammonia synthesized by glutamate dehydrogenase, which converts glutamic acid to α- ketoglutarate and ammonia (Figure 1). In the analysis of plasma amino acid levels, we detected low ornithine levels with carglumic acid treatment compared to other nitrogen scavenger treatments. It may be explained by the activation of CPS1 with carglumic acid. Activated CPS1 causes increased concentration of carbamoyl phosphate, which is catalysed by OTC with ornithine to form citrulline and phosphate. This pathway supports a decrease in plasma ornithine levels. Furthermore, the expected increase in plasma citrulline levels during carglumic acid treatment was not detected in our patient. We hypothesize that the high rate of urinary citrulline excretion prevents elevated plasma citrulline levels (Figure 1). However, we have no data regarding the urinary citrulline levels of our patient to verify our hypothesis. Basically, urinary excretion of citrulline allows the use of carglumic acid in the treatment of hyperammonaemia in argininosuccinate synthetase deficiency as citrulline and argininosuccinate are excreted by kidneys (Figure 1). 17 In the light of these data, our case suggests that carglumic acid may also be used for the treatment of hyperammonaemia in patients with argininosuccinate lyase deficiency. To date, no information has been obtained about the use of carglumic acid in

5 128 KOSE et al. argininosuccinate lyase deficiency. Clinical studies, as well as measurement of ureagenesis, are warranted to demonstrate a possible effect of carglumic acid treatment in argininosuccinate lyase deficiency. There are several limitations in this manuscript. In this case, we did not analyse the serum glutamine levels of the patient due to technical inadequacy. Instead of serum glutamic acid, serum glutamine level may give more information about the urinary cycle pathway. In addition, absence of urinary amino acid levels makes understanding the effect of carglumic acid in citrullinemia type 1 difficult. Finally, our hypothesis related to the therapeutic pathway of carglumic acid in citrullinemia patients should be tested using stable isotope- based quantification of ureagenesis. 2.2 Statistical analysis The Friedman test (nonparametric repeated- measures comparisons) was performed for the analysis of plasma ammonia, glycine, glutamic acid, citrulline and ornithine levels of the patient. A P- value <.05 was considered significant. 3 WHAT IS NEW AND CONCLUSION In conclusion, this is the first case of citrullinemia type 1 for whom follow- up was performed with carglumic acid treatment. Our case provides insight on the efficacy of carglumic acid in the long- term treatment of citrullinemia type 1. However, further studies with larger cohorts would be important to confirm the efficacy and safety of carglumic acid in this condition. ACKNOWLEDGEMENT We thank the parents of our patient for their consent. Written informed consent was obtained from the parents of our case before writing the manuscript. The study has not received any external funding from any public or private institutions. Mutation analysis at University Children s Hospital Zurich is supported by the Swiss National Science Foundation (grant _ to JH). CONFLICT OF INTEREST The authors report no conflict of interests. The authors alone are responsible for the content and writing of the manuscript. REFERENCES 1. Auron A, Brophy PD. Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol. 2012;27: Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;29: Häberle J. Role of carglumic acid in the treatment of acute hyperammonemia due to N- acetylglutamate synthase deficiency. Ther Clin Risk Manag. 2011;7: Chapel-Crespo CC, Diaz GA, Oishi K. Efficacy of N- carbamoyl- L- glutamic acid for the treatment of inherited metabolic disorders. Expert Rev Endocrinol Metab. 2016;11: Ah Mew N, McCarter R, Daikhin Y, et al. Augmenting ureagenesis in patients with partial carbamyl phosphate synthetase 1 deficiency with N- carbamyl- L- glutamate. J Pediatr. 2014;165: Ah Mew N, Payan I, Daikhin Y, et al. Effects of a single dose of N- carbamylglutamate on the rate of ureagenesis. Mol Genet Metab. 2009;98: Filippi L, Gozzini E, Fiorini P, Malvagia S, la Marca G, Donati MA. N- carbamylglutamate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria. Neonatology. 2010;97: Lévesque S, Karalis A, Lambert M, Russell L. Outcome of propionic acidemia treated at presentation with N- carbamylglutamate (abstract). Mol Genet Metab. 2010;99: Kasapkara CS, Ezgu FS, Okur I, Tumer L, Biberoglu G, Hasanoglu A. N- carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia. Eur J Pediatr. 2011;170: Aires CC, van Cruchten A, Ijlst L, et al. New insights on the mechanisms of valproate- induced hyperammonemia: inhibition of hepatic N- acetylglutamate synthase activity by valproyl- CoA. J Hepatol. 2011;55: Williams CA, Tiefenbach S, McReynolds JW. Valproic acidinduced hyperammonemia in mentally retarded adults. Neurology. 1984;34: Valayannopoulos V, Baruteau J, Delgado MB, et al. Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk- benefit profile: a retrospective observational study. Orphanet J Rare Dis. 2016;11: Martín-Hernández E, Aldámiz-Echevarría L, Castejón-Ponce E, et al. Urea cycle disorders in Spain: an observational, cross- sectional and multicentric study of 104 cases. Orphanet J Rare Dis. 2014;9: Thompson CA. Carglumic acid approved to treat genetic hyperammonemia. Am J Health Syst Pharm. 2010;67: Yudkoff M, Ah Mew N, Daikhin Y, et al. Measuring in vivo ureagenesis with stable isotopes. Mol Genet Metab. 2010;100: Matoori S, Leroux JC. Recent advances in the treatment of hyperammonemia. Adv Drug Deliv Rev. 2015;90: van de Poll MC, Soeters PB, Deutz NE, Fearon KC, Dejong CH. Renal metabolism of amino acids: its role in interorgan amino acid exchange. Am J Clin Nutr. 2004;79: How to cite this article: Kose E, Kuyum P, Aksoy B, Häberle J, Arslan N, Ozturk Y. First report of carglumic acid in a patient with citrullinemia type 1 (argininosuccinate synthetase deficiency). J Clin Pharm Ther. 2018;43: org/ /jcpt.12593